Synonym: PF02341066; PF-02341066; PF 02341066; PF2341066; PF-2341066; PF 2341066; Crizotinib; US brand name: Xalkori;

IUPAC/Chemical Name: (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

InChi Key: KTEIFNKAUNYNJU-GFCCVEGCSA-N

InChi Code: InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1

SMILES Code: NC1=NC=C(C2=CN(C3CCNCC3)N=C2)C=C1O[C@@H](C4=C(Cl)C=CC(F)=C4Cl)C

Technical Data

Additional Information

1.  Crizotinib's phyisical and chemical properties:
Crizotinib is a white to pale-yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation).
   
2 . The solubility of crizotinib:
The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10 mg/mL to less than 0.1 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.
 
3. Mechanism of action:
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and Recepteur d'Origine Nantais (RON). Crizotinib has an aminopyridine structure, and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases . Crizotinib demonstrated concentration-dependent inhibition of ALK and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met.
 
Crizotinib also inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms. Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells. Other studies suggest that crizotinib may also act via inhibition of angiogenesis in malignant tumors.(source: http://en.wikipedia.org/wiki/Crizotinib).

On August 26, 2011, the U.S. Food and Drug Administration approved crizotinib (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene.
     
 

References

1: Ou SH, Tong WP, Azada M, Siwak-Tapp C, Dy J, Stiber JA. Heart rate decrease during crizotinib treatment and potential correlation to clinical response. Cancer. 2013 Mar 15. doi: 10.1002/cncr.28040. [Epub ahead of print] PubMed PMID: 23505007.

2: Kaneda H, Okamoto I, Nakagawa K. Rapid Response of Brain Metastasis to Crizotinib in a Patient with ALK Rearrangement-Positive Non-Small-Cell Lung Cancer. J Thorac Oncol. 2013 Apr;8(4):e32-3. doi: 10.1097/JTO.0b013e3182843771. PubMed PMID: 23486271.

3: Maillet D, Martel-Lafay I, Arpin D, Pérol M. Ineffectiveness of Crizotinib on Brain Metastases in Two Cases of Lung Adenocarcinoma with EML4-ALK Rearrangement. J Thorac Oncol. 2013 Apr;8(4):e30-1. doi: 10.1097/JTO.0b013e318288dc2d. PubMed PMID: 23486270.

4: Pilotto S, Peretti U, Novello S, Rossi G, Milella M, Giaj Levra M, Ciuffreda L, Massari F, Brunelli M, Tortora G, Bria E. PROFILing non-small-cell lung cancer patients for treatment with crizotinib according to anaplastic lymphoma kinase abnormalities: translating science into medicine. Expert Opin Pharmacother. 2013 Apr;14(5):597-608. doi: 10.1517/14656566.2013.778828. Epub 2013 Mar 9. PubMed PMID: 23472711.

5: Sun Y, Nowak KA, Zaorsky NG, Winchester CL, Dalal K, Giacalone NJ, Liu N, Werner-Wasik M, Wasik MA, Dicker AP, Lu B. ALK inhibitor PF02341066 (crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK. Mol Cancer Ther. 2013 Feb 26. [Epub ahead of print] PubMed PMID: 23443800.

6: Huang D, Kim DW, Kotsakis A, Deng S, Lira P, Ho SN, Lee NV, Vizcarra P, Cao JQ, Christensen JG, Kim TM, Sun JM, Ahn JS, Ahn MJ, Park K, Mao M. Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment. Genomics. 2013 Feb 20. doi:pii: S0888-7543(13)00034-7. 10.1016/j.ygeno.2013.02.006. [Epub ahead of print] PubMed PMID: 23434628.

7: Zheng X, He K, Zhang L, Yu J. Crizotinib induces PUMA-dependent apoptosis in colon cancer cells. Mol Cancer Ther. 2013 Feb 20. [Epub ahead of print] PubMed PMID: 23427294.

8: Srivastava N, VanderLaan PA, Kelly CP, Costa DB. Esophagitis: a novel adverse event of crizotinib in a patient with ALK-positive non-small-cell lung cancer. J Thorac Oncol. 2013 Mar;8(3):e23-4. doi: 10.1097/JTO.0b013e31827e2451. PubMed PMID: 23407563.

9: Browning ET, Weickhardt AJ, Camidge DR. Response to crizotinib rechallenge after initial progression and intervening chemotherapy in ALK lung cancer. J Thorac Oncol. 2013 Mar;8(3):e21. doi: 10.1097/JTO.0b013e31827a892c. PubMed PMID: 23407562.

10: Nonaka S, Yamaguchi S, Nagasawa T, Tahara M. [Pharmacology profile of crizotinib (Xalkori(®)Capsules) and clinical findings on this drug]. Nihon Yakurigaku Zasshi. 2013 Feb;141(2):106-13. Japanese. PubMed PMID: 23391552.